Research Interests 

Dynamics of Chromatin Remodelling

The higher-order organisation of chromatin governs and dictates the regulation of several cellular processes involving DNA. ATP-dependent chromatin remodelling complexes (CRCs) and modifying enzymes are important protein machineries that remodel or modify the higher-order chromatin structure to sense and repair DNA damage. Chromatin constitutes a physical barrier to DNA repair machineries from reaching the DNA. To address this, transient chromatin structural changes are integral to various DNA repair pathways. However, the relation between CRCs and DNA repair proteins is not completely understood. Several studies show that INO80 CRC, found in eukaryotes, contains actin and several actin-related proteins, which play important roles in homologous recombination and DNA repair. Our laboratory is interested in examining the roles of Actin-Related Proteins (ARPs) and the INO80 family of CRCs in chromatin remodelling with the aim of understanding their molecular mechanisms in chromatin targeting and remodelling. To fully understand the mechanism of action of chromatin remodelling complexes, it will be necessary to determine how their activities are regulated, how they are targeted to specific genes, and how they interact with histone-modifying enzymes and other regulatory proteins that modulate chromatin. Our laboratory uses model organisms such as Saccharomyces cerevisiae, and  Ustilago maydis to address these important issues.

Mycobacterium tuberculosis (Mtb) is equipped with an arsenal of transcriptional regulators, stress responses and DNA repair mechanisms. These DNA repair mechanisms, otherwise known as the DNA damage response (DDR), fall into two categories: the Canonical SOS pathway and the Non-canonical pathway. The latter comprises the PafBC and ClpR pathways. The canonical "SOS" response is regulated by the master regulators, the repressor LexA and the co-activator RecA (recombinase A). This pathway also harbours DnaE2, an error-prone polymerase, one of the well-studied components of the mycobacterial mutasome machinery and a major cause of Antimicrobial resistance (AMR) in Mtb. The non-canonical PafBC pathway is regulated by a complex consisting of PafB and PafC. PafBC activates around 150 genes in response to Mitomycin C (MMC) stress. These genes are involved in replication, recombination and repair. Our lab focuses on understanding regulatory mechanisms of these master regulators and their interplay among LexA, RecA and PafBC. We also work to identify novel chemical inhibitors of these regulators as tools to disrupt these major stress response pathways and combat AMR.

In response to continuous DNA damage, the bacterial cells employ specific DNA repair systems that help maintain genome integrity. The first response towards DNA damage is the induction of SOS response, which involves expression of several genes, which participate in a variety of DNA metabolic activities such as replication, repair, recombination and mutagenesis. Under normal growth conditions the SOS genes are expressed at a basal level, which increases distinctly upon induction of the SOS response in many bacterial species including Mtb.  Mtb are a dreadful pathogen which survives within the hostile environment of macrophage; hence it is not surprising that it would employ a highly efficient DNA repair machinery to exist in such an environment.  Mycobacterial genome contains several putative HNH Nucleases, Toxin-Antitoxin module and Methyltransferases under the SOS regulon. Our lab is focused to understand the role of SOS regulated Nucleases in DNA repair. Investigation of these Nucleases will provide a new direction to our understanding of Mycobacterial DNA repair and also the strategy it adopts to survive within the macrophages. ​